biochimistry of ketoacidosis

1. KETOACIDOSIS

2. INTRODUCTION
• Carbohydrates are essential for the metabolism of fat or FAT is
burned under the fire of carbohydrates.
• Acetyl CoA formed from fatty acids can enter & get oxidized in
TCA cycle only when carbohydrates are available.
• During starvation & diabetes mellitus, acetyl CoA takes the
alternate route of formation of ketone bodies

3. Ketone body are three water solubele molecules that are
produced by the liver from oxidation of fatty acids through
process of ketogenesis .
Ketogenesis is a process of production occur during periods
of low food intake (fasting), starvation, prolonged intense
exercise, or in type 1 diabetes mellitus.
INTRODUCTION

4. Ketogenesis is a physiologic process , it becomes pathologic
when there is an excess production of ketone bodies
(ketoacidosis) .
Ketoacidosis is a metabolic state associated with high
concentration of ketone bodies formed by the oxidation of fatty
acid .

5. Chemistry of ketones :-
It is composed of three molecules (Acetoacetate ,
beta-hydroxybutyrate, acetone ).
acetone can not be used by the body and is highly
volatile so it is exhaled and also excreted in urine .
Precursor of ketones is acetyl-co A ,after producing
acetyl-coA by oxidation of fatty acid it is converted to
these three molecule (ketone ).

6. Ketogenesis

7. Uses of ketones :-
• Heart muscle & renal cortex also utilizes ketone bodies
as fuel, if glucose is not available.
• Almost all tissues (intestinal mucosal cells, placenta &
adipocytes) & cells utilizes ketone bodies as fuel, except
liver & RBC.
Why ketones can not be used as a source
of energy in liver
Because the liver lack thiophorase that is necessary for
oxidation of acetoacetate (conversion of acetoacetate to
acetyl coA) .

8. Compared to glucose, ketone bodies are an ideal
energy substrate for the brain as they supply more
energy per oxygen consumed, provide energy at a
faster rate and regulate energy levels.
Ketoacidosis is a pathological process
generated from :-
• starvation
• diabetes
• alcoholism

9. Types of ketoacidosis :-
Diabetic ketoacidosis:
• Untreated DM is the most common cause.
• DM is associated with insulin deficiency, causes the
accelerated lipolysis & more fatty acids are released into
circulation.
• Oxidation of these FA increases Acetyl CoA.
• Enhanced gluconeogenesis restricts the oxidation of acetyl
CoA by TCA cycle.
• Since availability of oxaloacetate is less.
• Finally, acetyl CoA is diverted for ketone bodies synthesis
in DM.

10. Symptoms :-
-frequent urination(osmotic diuresis)
-extreme thirst(dehydration)
-high blood sugar levels(insulin deficiency)
-high levels of ketones in the urine

11. Treatment of DKA :-
• Correction of hyperglycemia with insulin
• Correction of fluid loss with intravenous fluids
• Correction of electrolyte disturbances, particularly
potassium loss
• Correction of acid-base balance

12. Alcoholic ketoacidosis(AKA):-
is a metabolic complication of alcohol use characterized by
hyperketonemia and metabolic acidosis without significant
hyperglycemia (why) .
Because alchohol block the first step of gluconeogenesis
by depleting oxaloacetate.
Thus the body can not produce
Enough glucose to meet its energy
Creating an energy crisis resulting
In fatty acid metabolization and
ketone body formation .

13. Symptoms:-
Vomiting , nausea , slow movement , fatigue ,
the 3 major pathophysiologic causes of the
AKA, are :-
1-Extracellular fluid volume depletion .
2-Glycogen depletion .
3-An elevated ratio of the reduced form of nicotinamide
adenine dinucleotide (NADH) to nicotinamide adenine
dinucleotide (NAD +) .

14. Management:-
The greatest threats to patients with alcoholic ketoacidosis
are marked contraction in extracellular fluid volume
(resulting in shock), hypokalaemia , hypoglycaemia, and
acidosis .
Management summarized in :-
Potassium supplementation.
Mg & Phosphate supplementation.
Intravenous rehydration .

15. Starvation ketoacidosis :-
• In starvation, the dietary supply of glucose is
decreased
• Starvation is accompanied by increased
degradation of fatty acids.
• During prolonged starvation, ketone bodies are the
major fuel source for the brain & other parts of
central nervous system

16. • Available oxaloacetate is channeled to gluconeogenesis.
• Increased rate of lipolysis is to provide alternate source
of fuel.
• The excess acetyl CoA is converted to ketone bodies.
• The high glucagon favors ketogenesis.
• The brain derives 75% of energy from ketone bodies
under conditions of fasting

17. • Hypermesis (vomiting) in early pregnancy may also
lead to starvation-like condition & may lead to ketosis.
• Glucagon-ketogenesis:
• During starvation & DM, level of glucagon is
increased.
• Glucagon inhibits glycolysis, activates
gluconeogenesis & lipolysis, decreases malonyl CoA
level & stimulates ketogenesis.

18. REGULATION OF KETOGENESIS
• The ketone body formation (particularly
overproduction) occurs primarily due to
nonavailability of carbohydrates to the tissues.
• The hormone glucagon stimulates ketogenesis
whereas insulin inhibits.
• The increased ratio of glucagon/insulin in diabetes
mellitus promotes ketone body formation. This is due
to disturbances caused in carbohydrate and lipid
metabolisms in diabetes.

19. The ketone body formation is regulated at Three levels:
1. Lipolysis:
• Free fatty acids are the precursors of ketone bodies.
• Factors regulating the mobilization of fatty acid from
adipose tissue will also control ketogenesis.
• Insulin inhibits lipolysis, while glucagon favors
lipolysis.

20. 2. Entry of fatty acids to mitochondria:
• The mobilized fatty acid then enters mitochondria for
β-oxidation.
• CAT 1( carnitine acyltransferase I) regulates this entry.
• Malonyl CoA is the major regulator of CAT-1 activity.
• In diabetes & starvation, glucagon is increased, which
decreases malonyl CoA & β- oxidation is stimulated.

21. 3. Oxidation of Acetyl CoA:
• When above two steps are increased, more acetyl CoA
is produced.
• Acetyl CoA is completely oxidized in TCA cycle.
• In DM & starvation, glucagon/insulin ratio is
increased & key gluconeogenic enzymes are activated.

22. When Oxaloacetate is diverted to gluconeogenesis
• TCA cycle cannot function optimally.
• Acetyl CoA is generated in excess & its utilization is
reduced.
• This excess acetyl CoA is channeled into ketogenic
pathway.
• In both DM & starvation, the oxaloacetate is
channeled to gluconeogenesis.
• The availability of oxaloacetate is decreased
• Hence acetyl CoA cannot be fully oxidized in the TCA
cycle.

23. REFERENCES:
• Netter’s Physiology Flash Cards
• NETTER’S ESSENTIAL PHYSIOLOGY
• Davidsons Principles and practice of medicine_22Ed
• Lippincott's Illustrated Reviews Biochemistry 5th edition
• Guyton_and_Hall_Textbook_of_Medical
• Gannon's Review of Medical Physiology
• Medscape website
• Lippincott Illustrated Reviews: Pharmacology Sixth Edition
• WebMD website